REVIEW ARTICLE

Advantages using arginine and glutamine combination in sepsis patients

Introduction

Sepsis is a life-threatening organ dysfunction associated with a dysregulated host

response to infection.1 It is a leading cause of death due to multiple organ failure (MOF)

in critically ill patients.2 Sepsis affects 300million people annually and is a cause of
death in more than 200,000 patients, making it the tenth most common cause of death in
the United States. Glutamine and arginine amino acids have both roles on growth, tissue
3
repair, cell renewal and collagene synthesis . Glutamine is the most abundant amino
acid but its storage is immediately depleted from muscles in catabolic stages such as
trauma, sepsis and burn. For this reason glutamine is defined as con- ditionally essantial.
Arginine has also roles in nitrogene metabolism, creatine and polyamine synthesis and is
the major sub- strate for nitric oxide synthesis. Thus it has an important role on immune
response. Arginine is not an essential amino acid for healthy subjects, but in stress phases
such as sepsis, it might be essential. 4 Low plasma arginine levels and increased arginine
requirement which could not be met by endogenous synthesis in septic patients are
related with worsening prognosis.5,6 Prevalance of hospital deaths caused by sepsis has
been incresing as 90% since last 20 years. Sepsis and inflammation cause multiple organ
dysfunction syndrome (MODS) which is usually the cause for death in intensive care
units. Decreasing or inhibiting stress response with substrats like glutamine may help pre-
venting from MODS thus mortality in critically ill patients. 7 The results of animal models
of arginine supple- mentation in sepsis are unsteady. The results are almost the equal mix
of benefit, harm and no effect.8 Heyland et al. 9 have published a meta-analysis indicating
that arginine supplemented diets have no benefit even might be harmful and have
potential side effects in 2001, while in elective surgery patients arginine supplementation
is found to be benefical by decreasing infection risk.10
ARGININE

Arginine is classified as a nonessential amino acid in healthy individuals.

However, arginine can become a conditionally essential amino acid during metabolic or
traumatic stress because the endogenous arginine supply is inadequate to meet

physiological demands.11 Arginine depletion during critical illness may have several
important effects, including reduced NO production, poor wound healing, impaired
microcirculatory blood flow, immunosuppression (T-cell dysfunction), and impaired

muscle function.12,13 However, evidence of a benefit of arginine administration in ICU

patients is still lacking.13 Tadié et al showed that early enteral L-arginine administration
does not reverse immunosuppression or inflammation in medi- cal ICU (MICU)

patients.14

Luiking et al also reported no effect on global hemodynamics, organ function

parameters or protein metabolism by L-arginine infusion in severe sepsis patients. 15

However, a previous study reported that using an arginine-supplemented diet in
perioperative patients reduced infection and the hospital LOS but had no significant

effect on mortality.16

Glutamine

Glutamine is among the most abundant amino acids and is classified as a

nonessential amino acid in the human body. However, glutamine may become a
conditionally essential amino acid during stress. Glutamine is an important oxidative fuel
for rapidly proliferating cells, including those in the gastrointestinal tract and immune
system, and mainly serves as a precursor in the synthesis of other amino acids and

glucose for energy.12 In addition, glutamine seems to be a potent enhancer of stress-

induced heat shock protein expression, which can decrease cell death and organ injuries

in several models of cellular stress.13Numerous studies investigating the effects of

glutamine have been published over the past years. Two major meta-analyses illustrated
the positive effect of glutamine before 2014. Bollhalder et al analyzed forty randomized
clinical trials and reported no significant reduction in short-term mortality but found
reduced infection and hospital LOS with parenteral glutamine supplementation in

severely ill patients.14 Wischmeyer et al also analyzed 26 RCTs and reported that
parenteral glutamine supplementation was associated with a significant reduction in

hospital mortality and the hospital LOS. 15 However, this beneficial effect was only
observed in single-center studies and not in multicenter studies during the subgroup
analysis.

Since 2013, several strong studies investigating the negative influence of

glutamine have been published. One multicountry, multicentered large RCT (1223
critically ill patients in 40 ICUs who received supplements of glutamine, antioxidants,
both, or placebo), the REDOXS study, reported that the early provision of glutamine did
not improve survival and was associated with an increase in mortality among critically ill

patients with multiorgan failure.16,17 Another MetaPlus study compared high-protein EN

enriched with immune-modulating nutrients (IMHP, including glutamine, omega-3 fatty
acids, and antioxidants) to standard high-protein EN (HP) in mechanically ventilated
critically ill patients. The results showed that the IMHP group did not show
improvements in infectious complications but had a higher 6-month mortality rate than

the medical subgroup.18 A recent meta- analysis also reported that enteral glutamine
provision resulted in no significant difference in mortality or the length of

hospitalization.19 However, some evidence has proven that glutamine has benefits in
subgroups of critical patients. Glutamine supplemented EN could be associated with a
reduction in hospital mortality and bacteremia in burn patients and a reduction in

infectious complications in multiple- trauma patients. 20,21 Finally, Stehle et al published

a metaanalysis (15 RCTs involving 842 patients) of studies that enrolled only
hemodynamically stable patients without liver or renal failure. The conclusion showed
that parent- eral glutamine dipeptide supplementation significantly reduced infectious
 complications, the ICU LOS, the hoapital LOS, and the mechanical ventilation duration

and lowered the hospital mortality rate by 45% but had no effect on ICU mortality. 22 In
conclusion, supplemental glutamine might be used cautiously in surgical patients with

burns or multiple traumas and stable medical patients. 23 The current published
nutritional guidelines also have conservative recommendations for glutamine use in
critical patients.

L-Arginine supplementation human in patients with sepsis

Human studies have largely been conducted using immune-enhancing diets (IEDs)
containing relatively high concentrations of L-arginine. As such, the effects of L-arginine per se
in these complex formulas cannot be determined with any certainty. Here we will discuss the
major studies that are relevant to this review. The reader is referred to meta-analyses and other
authoritative commentaries on these studies that express a variety of opinions and interpretations
26,27.
Galban et al. 28 evaluated whether early enteral feeding with high L-arginine content, mRNA,
and v-3 fatty acids from fish oil would improve clinical outcomes. The study was randomized
and performed in six intensive-care units (ICUs). Notably, it is the largest study performed to
date specifically focused on a target population of septic patients. Patients with sepsis and
APACHE II scores equal or greater than 10 were randomized to the experimental arm to receive
L-arginine-enriched enteral feeding or to the control to receive regular high-protein diet. The
intention-to-treat analysis of 176 patients showed a significant reduction in bacteremic episodes
and mortality (32 compared with 19%). Most of the survival benefit was seen in the group with
the lowest APACHE II scores (10 – 15), and the length of ICU stay was not changed by the
experimental diet. All the remaining clinical studies described below examined mixed ICU
patient populations, including a subgroup of patients with sepsis. Atkinson et al. performed a
double-blinded, randomized study evaluating a diet enriched with L-arginine, mRNA, and v-3
fatty acids against an isocaloric, isonitrogenous enteral feed in a single ICU. The overall results
showed no significant differences between the study arms (48% for the IED and 44% for the
control). In subgroup analysis of subjects receiving a critical amount of nutrition, the
experimental diet significantly reduced the duration of mechanical ventilation and length of
hospital stay. However, the conclusion that this sub- group analysis demonstrated benefit has
been ques- tioned, because of a trend toward increased mortality. 46.

Caparros et al. 31performed a randomized, singleblinded study in 15 ICUs comparing a

high-protein diet enriched with L-arginine, fiber, and antioxidants against a standard high-protein
diet with respect to clinical outomes in 220 patients. No differences were found between both
groups among the following variables: ventilator-associated pneumonia, surgical infection, bac-
teremia, and ICU or in-hospital mortality. However, catheter-related infections were significantly
32
reduced in the group receiving experimental diet. More recently, Bertolini et al. randomized
237 patients from 33 ICUs to enteral immunonutrition or standard total parenteral nutrition. The
ICU mortality in the small subgroup of patients with severe sepsis was significantly higher in the
patients receiving enteral compared with parenteral feeding /Baseline differences did not appear
to explain these results. Due to these interim analysis results, the enrolment of patients with
severe sepsis was halted. 33

The largest randomized, double-blinded, controlled trial evaluating a dietary formula enriched
with L-arginine (and other nutrients) against an isocaloric, non-isonitro- genous standard enteral
formula was recently published by Kieft et al. . A total of 597 patients were random-ized and 473
received their assigned therapy meeting criteria for the per-protocol analysis. Infectious compli
cations, length of ICU stay, mechanical ventilation duration, ICU mortality, and hospital
mortality were not significantly different between both study groups. In fact, mechanical
ventilation duration, length of stay, and mortality were non-significantly increased in the
experimental arm compared with the control. However, baseline imbalances such as age and site
of infection were present in the study and may have biased some of these results. 34

Glutamin Supplementation

In a meta-analysis evaluating four randomised controlled trials with glutamine has shown that
high prevalance of infectous complications are caused by intestinal permeability, colonic
apoptosis and decreased secretuar immunglobulin A function, abnormal lymphosyte and
macrophage functions and glutamine supplementation might reverese all these
effects.35Parenteral glutamine administration for four weeks to rats with protein energy
malnutrition decreased inflammation and prevented from organ damage due to sepsis. 36 In
another study on rats evaluating the effects of glutamine on intestinal functions has shown that
decreasing amino acid concentration due to endo- toxemia is related with enterocyte dysfunction,
thus oral or enteral glutamine supplementation could not be as effective as parenteral glutamine
37
administration due to impaired intestinal capasity Differently, a study investigating
intraabdominal sepsis model in rats has shown that enteral glu- tamine supplementation
decreases bacterial transloca-tion and increases mucosal thickness and antioxidant levels. 38.
Another study in rats also determined that enteral glutamine does not prevent from bacte- rial
translocation but significatntly decreases bacterial spread.. 39 A study investigating the effects of
glutamine on cytokine formation has shown that lipopolysaccharide injection to blood samples of
healthy subjects and glutamine administration to endotoxemic blood samples might have positive
effects on mortality and morbidity. 40

Combination L-arginine & Glutamine in septic of the role of tight junction

Critical illness may induce endothelial TJ disruption through mechanical, ischemic, or

overwhelming inflammatory insults. stimulation may lead to the active disassembly of
endothelial TJs, as is presumed to occur in capillary leak associated with septic shock. Serum
ZO-1, occludin, and zonulin are all elevated in sepsis; however, ZO-1 best stratified sepsis
severity and degree of organ dysfunction. That ZO-1 outperformed other TJ markers may reflect
the con- comitant organ epithelial injury which occurs in multiple organ dysfunction syndrome.
Similarly, in Dengue fever, serum levels correlated with the amount of plasma leakage,
demonstrating its specificity as a biomarker of vascular barrier dysfunction. A number of
clinical factors may initiate destabilization of epithelial and endothelial barriers in critical illness,
such as overwhelming or unrelenting stimulation from in- flammatory (i.e., cytokines), hypoxic-
ischemic or traumatic insults (i.e., damage-associ- ated molecular patterns). Yet, regardless of
the particular instigating factors, injured endothelial and epithelial TJs may share a common
molecular pathway of active there has been minimal investigation on the use of TJ markers in
cardiac or pulmonary failure, a glaring lapse given its high prevalence and the associated
morbid- ity and mortality. or ELISA), to guide researchers, nor have many of these tests been
validated in the clin-ical setting. Identifying the optimal detection methods for TJ proteins, and
adapting such tests to the appropriate clinical specimens, present opportunities to advance this
line of research. Ultimately, markers of TJ disruption may have the potential to provide
clinicians with more precise information to assist in the diagnosis, management, and improved
pathophysiologic understanding of diseases such as capillary leak, pulmonary edema, and
multiple organ dysfunction syndrome. Intravenous or oral glutamine supplementation has been
associated with a lower intestinal permeability but the mechanisms of action of glutamine
remained unknown. In addi- tion, other amino acids may also have beneficial effects during in-

testinal mucositis, i.e. taurine,11 or during intestinal inflammation, i.e. arginine or glycine .10
Glutamine, arginine, glutamate and leu- cine were able to limit barrier disruption induced by
MTX in Caco-2 cells compared with other tested amino acids. Citrulline also showed a trend but
difference did not reach significance. Our results are in accordance with previous data showing
that glutamine was able to modulate TJs protein expression and localization during glutamine
deprivation in Caco-2 cells. The combination gluta- mine plus arginine was the most effective to
reverse the decrease of TEER induced by MTX compared with glutamineeleucine or
glutamineearginineeleucine combinations. These data suggest that leucine may antagonize the
beneficial effects of glutamine or of arginine. In addition, glutamineearginine combination did
not provide additive or synergic effects because similar results were observed with glutamine
alone glutamine and arginine have been previously studied but provided different results
according to the used experimental model. In healthy newborn rats, arginine reduced the

beneficial effects of glutamine on oxidative stress. 34 In contrast, either during gut- derived

sepsis in mice,21 in colonic mucosa of Crohn’s patients 22 or in IgE-activated mast cells ,35
combined glutamine and arginine had enhanced protective effects compared with arginine or
gluta-mine alone. These discrepancies between studies may be due to the different metabolic
pathways involved in the model. For instance, we recently speculated that glutamine and
arginine may have ad- ditive effects on immune response or on insulin resistance but not on
oxidative stress. Glutamine alone and glutamine plus arginine preserved paracellular
permeability, ZO-1 and occludin expression. Arginine alone also prevented the decrease of ZO-1
and occludin expression but in a lesser extent. In our study, arginine did not affect para- cellular
permeability. We can speculate that arginine effects on TJs protein expression were not sufficient
to restore intestinal per- meability. However, arginine may affect other parameters involved in
the occurrence of mucositis or may improve the recovery phase. For instance, in piglets during
enteritis, arginine increased protein synthesis rate in the mucosa of small intestine The effects of
glutamine and arginine supplementation on inflmammatory cytokines and intestinal mucosa in
lipopolysaccharide induced endotoxemia in rats are found that glutamine did not increase plasma
glutanmine and arginine levels while arginine supplementation increased plasma arginine levels.
Combination of glutammine and arginine could not increase plasma arginine levels as much as
arginine supplementation alone. 41

Oral supllementation of glutamine, arginine or their combina- tion all increased villus
lenght in jejenum and ileum and they had sinergetic effects on intestinal integrity and benefical
on inflammatory cytokines .41,42 Similarly we have found that the group supplemented with a
combination of glutamine and arginine amino acids had significantly lower levels of TNF-α in
comparison with control group. But there is a conflict that if the decrease in TNF-α levels was
due to the use of combination of these amino acids or due to the dose we have used for these
amino acids. 43-45

In combination group, rats recieved 250 mg/kg/day per amino acid with a total 500 mg/kg/day
while glutamine and arginine groups recieved 500 mg/kg/day glutamine or arginine. Present
literatüre emphasis that a dose of 500 mg/kg/day glutamine supplementation is benefical and a
range between 142-428 mg/kg/day is apropriate according toy he pathology while maximum
tolerated dose is 501 mg/kg/day when there is not any complication. As a result of supply of 250
mg/kg/day glutamine to rats in comparison with 500 mg/kg/day, it is found that 500 mg/kg/day is
more effective for decreasing the spread of E.coli, 2000 mg/kg/day supplementation of glutamine
with the aim of determining potential harm or toxicity has shown that even that dose did not
cause any side effects.46

These results support that the reason of highest IL-6 and TNF-α levels in glutamine group was
not caused by glutamine toxicity. It is also known that arginine is well tolorated by adult rats at
214-570 mg/kg/day doses . In a study investigating the effects of arginine doses on inflam-
mation it has been shown that a dose of 5000 mg/kg/ day arginine supplementation has a
significant antiinflammatory effect on peritoneal macrophages without any side effects. 43,44
A study investigating the effects of oral supple-mentation of glutamine and arginine on
inflammatory cytokines and intestinal mucosa has similar results with our study. 300 mg/kg/day
glutamine and arginine supplementation and a combination of these two ami- no acids 150
mg/kg/day per amino acid with a total of 300 mg/kg/day amino acid supplementation are com-
pared and it has been decided that the combination of these amino acids are more benefical on
intestinal mucosa and inflammatory cytokines. 44 Using half doses of glutamine and arginine in
combination group might be misleading as both of the amino acids have been discussed to have
potential harm in the present literature. In order to clarify, the study should be planned as all off
47
the groups are sup- pleented with the same dosed active ingredient. CRP is an acute phase
protein discovered in 1930. It adheres to Gram-positive and Gram-negative bac- teria and by this
way it helps leukocytes phagocyte them. CRP is produced in liver and peaks in 24-38 hours after
inflammation. While it is used in the diag- nosis of infectious and non-infectious inflammation, it
is not an optimal indicator for sepsis diagnosis. 48

In our study we found CRP levels in all groups between normal levels (negative according to
qualitative method). This might be due to that 24 hours period is not long enough for the
expected increase. Additionally, latex agglutination text is a qualitative method which is an easy
49
and low cost method but mildly sensitive and specific. Thus, the test method also might be the
reason for unexpected CRP levels.

We could not compare IL-1β levels between groups because we have found 250 pg/ml in all
gropus which was the maximum level that could be analysed in those concentrations. In order to
determine significant results, the samples should have been analysed at more diluted
concentrations.

Histopathological analysis of liver has shown that apsis, hepatocyte damage, kuppfer cell
proliferation and portal inflammation were significantly different between supplemented groups
and control group. Similarly, 7 days of 500 mg/kg/day paranteral glutamine supplementation has
found to decrease liver damage in rats with ischemia perfusion, In another model ischemia
perfusion, one dose of 750 mg/kg intraperitoneal glutamine administration, it is found that glu-
tamine protects liver from tissue damage and enteral gutamine supplemetation for 7 days at 1000
mg/ kg/day dose is found to be preventive from oxidative damage of liver. 47,49
CONCLUSION

Metabolic changes during sepsis indicate that combinations arginine & glutamine could be
considered as an essential amino acid in sepsis and that sepsis could be an arginine-deficient
state. Combination Arginine & Glutamine supplementation could subsequently be beneficial in
sepsis by improving microcirculation and protein anabolism. This hypothesis is further supported
by the detrimental effects of selective NOS2 inhibition in the hyperdynamic pig model of sepsis.
Moreover, combination supplementation in septic patients has transient effects on
hemodynamics when supplied as a bolus but has probably no hemodynamic side effects when
supplied continuously.

REFERENCES

1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions
journals.sagepub.com/home/tag for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315: 801–
810.
2. De Winter BY and De Man JG. Interplay between inflammation, immune system and neuronal
pathways: effect on gastrointestinal motility. World J Gastroenterol 2010; 16: 5523–5535.
3. Cheng Z, Buentello A, Gatlin III DM. Effetcs of dietary arginine and glutamine on growth
performance, immune re- sponses and intestinal structure of red drum, Sciaenops ocel- latus.
Aquaculture 2011; 319: 247-52.
4. Luiking YC, Poeze M, Dejong CH. Sepsis: an arginine defi- ciency state? Crit Care Med 2004;
32: 2135-45.
5. Freund H, Atamian S, Holroyde J. Plasma amino acids as predictors of the severity and outcome
of sepsis. Ann Surg 1979; 190: 571-6.
6. Kao CC, Bandi V, Guntupalli KK. Arginine, citrulline and nitric oxide metabolism in sepsis. Clin
Sci 2009; 117: 23-30.
7. Weitzel LB, Wischmeyer PE. Glutamine in critical illness: The time has come, the time is now.
Crit Care Clin 2010; 26: 515-25.
8. Zhou M, Martindale RG. Arginine in the critical care setting. J Nutr 2007; 137: 1687-92.
9. Heyland DK, Novak F, Drover JW. Should immunonutrition become routine in critically ill
patients? A systematic review of the evidence. JAMA 2001; 286: 944-53.
10. Drover JW, Dhaliwal R, Weitzel L. Perioperative use of arginine-suppemented diets: A
systematicreview of the evidence. J Am Coll Surg 2011; 212: 385-99.

11. Patel JJ, Miller KR, Rosenthal C, Rosenthal MD. When is it appro- priate to use arginine in
critical illness? Nutr Clin Pract. 2016;31 (4):438–444. doi:10.1177/0884533616652576.
12. Morris CR, Hamilton-Reeves J, Martindale RG, Sarav M, Ochoa Gautier JB. Acquired amino
acid deficiencies: a focus on arginine and glutamine. Nutr Clin Pract. 2017;32(1_suppl):30S–47S.
doi:10. 1177/0884533617691250.
13. Ginguay A, DeBandt JP, Cynober L. Indications and contraindica- tions for infusing specific
amino acids (leucine, glutamine, arginine, citrulline, and taurine) in critical illness. Curr Opin
Clin Nutr Metab Care. 2016;19(2):161–169.
14. Tadié JM, Cynober L, Peigne V, et al. Arginine administration to critically ill patients with a low
nitric oxide fraction in the airways: a pilot study. Intensive Care Med. 2013;39(9):1663–1665.
15. Luiking YC, Poeze M, Deutz NE. A randomized-controlled trial of arginine infusion in severe
sepsis on microcirculation and metabolism. Clin Nutr. 2020;39(6):1764–1773.
16. Drover JW, Dhaliwal R, Weitzel L, Wischmeyer PE, Ochoa JB, Heyland DK. Perioperative use
of arginine-supplemented diets: a systematic review of the evidence. J Am Coll Surg. 2011;212
(3):385–399.e1. doi:10.1016/j.jamcollsurg.2010.10.016.
17. Wischmeyer PE. Glutamine and heat shock protein expression. Nutrition. 2002;18(3):225–228.
doi:10.1016/S0899-9007(01)00796-1.
18. Bollhalder L, Pfeil AM, Tomonaga Y, Schwenkglenks M. A systematic literature review and
meta-analysis of randomized clinical trials of parenteral glutamine supplementation. Clin Nutr.
2013;32(2):213–223.
19. Wischmeyer PE, Dhaliwal R, McCall M, Ziegler TR, Heyland DK. Parenteral glutamine
supplementation in critical illness: a systematic review. Crit Care. 2014;18(2):1–17.

18 Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and

antioxidants in critically Ill patients. N Engl J Med. 2013;368(16):1489–1497.
19 Heyland DK, Elke G, Cook D, et al. Glutamine and antioxidants in the critically ill patient: a post
hoc analysis of a large-scale rando- mized Trial. J Parenter Enter Nutr. 2015;39(4):401–409..
20 Van Zanten ARH, Sztark F, Kaisers UX, et al. High-protein enteral nutrition enriched with
immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial
infections in the ICU: a randomized clinical trial. JAMA. 2014;312(5):514–524
21 Mottaghi A, Yeganeh MZ, Golzarand M, Jambarsang S, Mirmiran P. Efficacy of glutamine-
enriched enteral feeding formulae in critically ill patients: a systematic review and meta-analysis
of randomized controlled trials. Asia Pac J Clin Nutr. 2016;25(3):504–512.
22 Lin JJ, Chung XJ, Yang CY, Lau HL. A meta-analysis of trials using the intention to treat
principle for glutamine supplementation in critically ill patients with burn. Burns.
2013;39(4):565–570.
23 Hammarqvist F. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity
in patients with multiple trauma. JPEN J Parenter Enteral Nutr. 1999;23(1):43–44.
24 Stehle P, Ellger B, Kojic D, et al. Glutamine dipeptide-supplemented parenteral nutrition
improves the clinical outcomes of critically ill patients: a systematic evaluation of randomised
controlled trials. Clin Nutr ESPEN. 2017;17:75–85.
25 Wischmeyer PE. The glutamine debate in surgery and critical care. Curr Opin Crit Care.
2019;25(4):322–328
26 Heyland DK, Samis A. Does immunonutrition in patients with sepsis do more harm than good?
Intens Care Med 2003; 29:669 – 671.
27 Heyland DK, Novak F, Drover JW, et al. Should immunonutrition become routine in critically ill
patients? A systematic review of the evidence. JAMA 2001; 286:944–953.
28 Galban C, Montejo JC, Mesejo A, et al. An immune-enhancing enteral diet reduces mortality rate
and episodes of bacteremia in septic intensive care unit patients. Crit Care Med 2000; 28:643 –
648.
29 Atkinson S, Sieffert E, Bihari D. A prospective, randomized, double-blind, controlled clinical
trial of enteral immunonutrition in the critically ill Guy’s Hospital Intensive Care Group. Crit
Care Med 1998; 26:1164–1172.
30 Bower RH, Cerra FB, Bershadsky B, et al. Early enteral administration of a formula (Impact)
supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: results of a
multicenter, prospective, randomized, clinical trial. Crit Care Med 1995; 23:436–449.
31 Caparros T, Lopez J, Grau T. Early enteral nutrition in critically ill patients with a high-protein
diet enriched with arginine, fiber, and antioxidants compared with a standard high-protein diet
The effect on nosocomial infections and outcome. JPEN J Parenter Enteral Nutr 2001; 25:299–
308.
32 Dent D, Heyland D, Levy H. Immunonutrition may increase mortality in critically ill patients
with pneumonia: results of a randomized trial. Crit Care Med 2003; 30:A17.
33 Bertolini G, Iapichino G, Radrizzani D, et al. Early enteral immunonutrition in patients with
severe sepsis: results of an interim analysis of a randomized multicentre clinical trial. Intens Care
Med 2003; 29:834–840.
34 Kieft H, Roos AN, van Drunen JD, et al. Clinical outcome of immunonutrition in a heterogeneous
intensive care population. Intens Care Med 2005; 31:524– 532.
35 Lin J, Chung X, Yang C. A meta-analysis of trials using the intention to treat principle for
glutamine supplementa- tion in critically ill patients with burn. BURNS 2013; 39: 565-70.
36 Oliveira GP, Silva JD, Araujo CC. Intravenous glutamine administration reduces lung and distal
organ injury in mal- nourished rats with sepsis. Shock 2014; 41: 222-32.
37 Boutry C, Matsumoto H, Bos C. Decreased glutamate, glu- tamine and citrulline concentrations
in plasma and muscle in endotoxemia cannot be reversed by glutamate or glutamine
supplementation: a primary intestinal defect? Amino Acids 2012; 43: 1485-98.
38 Dönmez R, Ören D, Öztürk G. The combined effects of glutamine and growth hormone on
intestinal anastomosis in the rat intra-abdominal sepsis model. J Surg Res 2013; 182: 142-5.
39 Oliveira MA, Lemos DS, Diniz SOF. Prevention of bacte- rial translocation using glutamine: a
new strategy of investi- gation. Nutrition 2006; 22: 419-24.
40 Raspe C, Czeslick E, Weimann A. Glutamine and ala- nine-induced differential expression of
intracellular IL-6, IL-8 and TNF-α in LPS-stimulated monocytes in human whole-blood.
Cytokine 2013; 62: 52-7.
41 Heyland D, Muscedere J, Wischmeyer PE. A randomised trial of glutamine and antioxidants in
critically ill patients. N Engl J Med 2013; 368: 1489-97.
42 Bonhomme S, Belabed S, Blanc M. Arginine-supplemented enteral nutrition in critically ill
diabetic and obese rats: A dose ranging study evaluating nutritional status and mac- rophage
function. Nutrition 2013; 29: 305-12.
43 Prucha M, Bellingan G, Zazula R. Sepsis biomarkers. Clin Chim Acta 2015; 440: 97-103.
44 West BA, Peterside O, Ugwu RO. Prospective evaluation of the usefulness of C-reactive protein
in the diagnosis of neo- natal sepsis in a sub-Saharan African region. Antimicrobial Resistance
and Infection Control 2012; 1: 22.
45 Sezer A, Memiş D, Usta U. The effect of dexmedetomidine on liver histopathology in a rat
sepsis model: an experimen- tal pilot study. Ulus Travma Acil Cerrahi Derg 2010; 16: 108-12.
46 Sosnowski P, Krauss H, Bogdanski P. The influance of short-term L-arginine supplementation
on rats’ muscular and hepatic cells in ischemia-reperfusion syndrome. J Phys- iol Biochem 2012;
68: 1-9.
47 Stangl R, Szijarto A, Onody P. Reduction of liver ischemia- reperfusion injury via glutamine
pretreatment. J Surg Res 2011; 166: 95-103.
48 Sözen S, Kisakürek M, Yildiz F. The effects of glutamine on hepatic ischemia reperfusion injury
in rats. Hippokratia 2011; 15: 161-6.
49 Tihan DN, Erbil Y, Seven R. The effect of glutamine on oxidative damage in an experimental
abdominal compart- ment syndrome model in rats. Ulus Travma Acil Cerrahi Derg 2011; 17: 1-8.